The compound represented by the below-described formula (a) (which will hereinafter be abbreviated as Compound (a). Similar abbreviation will be applied to the compounds represented by other numbers), that is, (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-ben zo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione exhibits excellent antitumor activity and is therefore useful as an antitumor agent (refer to Japanese Patent Laid-Open No. HEI 6-87746). ##STR2##
The above compound can be obtained, for example, by the below-described synthesis route through the reaction between 8-amino-6-fluoro-5-methyl-2-trifluoroacetylamino-1-tetralone and (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10-(4H)t rione (refer to Japanese Patent Laid-Open No. HEI 6-87746). ##STR3##
(4S)-4-Alkyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10-(4H)-t rione (Compound (10)), which is one of the important intermediates for the preparation of the above compound, is known to be prepared, for example, in accordance with the following reaction scheme (J. Med. Chem., 554(1980)). ##STR4##
wherein R.sup.1 represents a C.sub.1-6 alkyl group, R.sup.2, R.sup.3, R.sup.4 and R.sup.6 each independently represents a C.sub.1-6 alkyl, aryl or aralkyl group, R.sup.5 represents a hydrogen atom or a C.sub.1-5 alkyl group, R.sup.5a represents a C.sub.1-5 alkyl group; and the reaction in the parentheses is that for obtaining Compound (7a) by alkylating Compound (7) when R.sup.5 is a hydrogen atom.
In the above reaction scheme, the reaction for obtaining 6-cyano-1,1-(ethylenedioxy)-7-[(alkoxycarbonyl)-alkyl]-5-oxo-.DELTA.6(8)-t etrahydroindolizine (7) from Compound (1) is reported by Wani et al. (J. Med. Chem., 554(1980)).
The method reported by Wani et al. is however accompanied with the problems such as prolonged reaction time, inferior operability and use of a dangerous reagent. Accordingly, there has been a demand for the development of an industrially superior preparation process.
Described specifically, the enol-etherification reaction for preparing Compound (2) from Compound (1) is effected in the presence of ammonium chloride as a catalyst and it takes even 7 days to complete the reaction. The subsequent cyclization reaction for preparing Compound (3) from Compound (2) is effected using acetone as a solvent, and it takes about 14 hours to complete this reaction. In the next cyclization reaction step for obtaining Compound (4) from Compound (3), dimethylformamide is used as a solvent and it takes as long as 40 hours for the reaction.
The ketalization reaction of Compound (5) is effected in the presence of p-toluenesulfonic acid as a catalyst in a solvent of toluene under azeotropic dehydration with ethylene glycol. This reaction is however accompanied with the problems that the solvent about 80 times the amount of the ketone (5) should be used twice, it takes 20 hours for the completion of the reaction, and the reaction needs cumbersome operation.
In the carbonylation reaction of Compound (6), toluene is used as a solvent and a metal hydride regarded as a dangerous reagent is used as a base. In addition, this step is accompanied with the problems that it includes a dropwise addition step and precipitation of crystals occurs during the reaction, which disturbs stirring.
Accordingly, an object of the present invention is to provide a process for preparing 6-cyano-1,1-(ethylene-dioxy)-7-[(alkoxycarbonyl)-alkyl]-5-oxo-.DELTA.6(8)- tetrahydroindolizine (7), which is a synthesis intermediate for the industrial preparation process of a camptothecin derivative (a), within a short time in a convenient manner.